RPTPζ/phosphacan is abnormally glycosylated in a model of muscle-eye-brain disease lacking functional POMGnT1

Neuroscience. 2012 Sep 18;220:47-61. doi: 10.1016/j.neuroscience.2012.06.026. Epub 2012 Jun 19.


Congenital muscular dystrophies (CMDs) with associated brain abnormalities are a group of disorders characterized by muscular dystrophy and brain and eye abnormalities that are frequently caused by mutations in known or putative glycotransferases involved in protein O-mannosyl glycosylation. Previous work identified α-dystroglycan as the major substrate for O-mannosylation and its altered glycosylation the major cause of these disorders. However, work from several labs indicated that other proteins in the brain are also O-mannosylated and therefore could contribute to CMD pathology in patients with mutations in the protein O-mannosylation pathway, however few of these proteins have been identified and fully characterized in CMDs. In this study we identify receptor protein tyrosine phosphatase ζ (RPTPζ) and its secreted variant, phosphacan, as another potentially important substrate for protein O-mannosylation in the brain. Using a mouse model of muscle-eye-brain disease lacking functional protein O-mannose β-1,2-N-acetylglucosaminyltransferase (POMGnT1), we show that RPTPζ/phosphacan is shifted to a lower molecular weight and distinct carbohydrate epitopes normally detected on the protein are either absent or substantially reduced, including Human Natural Killer-1 (HNK-1) reactivity. The spatial and temporal expression patterns of these O-mannosylated forms of RPTPζ/phosphacan and its hypoglycosylation and loss of HNK-1 glycan epitopes in POMGnT1 knockouts are suggestive of a role in the neural phenotypes observed in patients and animal models of CMDs.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Blotting, Western
  • Brain / metabolism*
  • Disease Models, Animal
  • Glycosylation
  • Immunohistochemistry
  • Immunoprecipitation
  • Mice
  • Mice, Knockout
  • N-Acetylglucosaminyltransferases / deficiency
  • Receptor-Like Protein Tyrosine Phosphatases, Class 5 / metabolism*
  • Walker-Warburg Syndrome / metabolism*


  • N-Acetylglucosaminyltransferases
  • protein O-mannose beta-1,2-N-acetylglucosaminyltransferase
  • Receptor-Like Protein Tyrosine Phosphatases, Class 5